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Characterization of potent fusion inhibitors of influenza virus.

  • Rowse M Department of Microbiology, University of Alabama at Birmingham, 1025 18th Street South, Birmingham, Alabama, 35294, United States of America.
  • Qiu S Department of Microbiology, University of Alabama at Birmingham, 1025 18th Street South, Birmingham, Alabama, 35294, United States of America.
  • Tsao J Department of Microbiology, University of Alabama at Birmingham, 1025 18th Street South, Birmingham, Alabama, 35294, United States of America.
  • Xian T Laboratory of Structural Biology, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • Khawaja S Institute of Biochemistry, ETH Zurich HPM E8.2, Otto-Stern-Weg 3, 8093 Zurich, Switzerland.
  • Yamauchi Y Institute of Biochemistry, ETH Zurich HPM E8.2, Otto-Stern-Weg 3, 8093 Zurich, Switzerland.
  • Yang Z Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • Wang G Laboratory of Structural Biology, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • Luo M Laboratory of Structural Biology, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Department of Chemistry, College of Arts and Sciences, Georgia State University, Atlanta, Georgia, 30302, United States of America.
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  • 2015-03-25
Published in:
  • PloS one. - 2015
Animals
Dogs
Electrophoresis, Polyacrylamide Gel
Fluorescence
HeLa Cells
Humans
Hydrogen-Ion Concentration
Influenza A Virus, H3N2 Subtype
Madin Darby Canine Kidney Cells
Microscopy, Electron
Norbornanes
Tetrazolium Salts
Thiazoles
Thiazolidines
Trypsin
Viral Fusion Protein Inhibitors
Viral Plaque Assay
Virion
Virus Internalization
English New inhibitors of influenza viruses are needed to combat the potential emergence of novel human influenza viruses. We have identified a class of small molecules that inhibit replication of influenza virus at picomolar concentrations in plaque reduction assays. The compound also inhibits replication of vesicular stomatitis virus. Time of addition and dilution experiments with influenza virus indicated that an early time point of infection was blocked and that inhibitor 136 tightly bound to virions. Using fluorescently labeled influenza virus, inhibition of viral fusion to cellular membranes by blocked lipid mixing was established as the mechanism of action for this class of inhibitors. Stabilization of the neutral pH form of hemagglutinin (HA) was ruled out by trypsin digestion studies in vitro and with conformation specific HA antibodies within cells. Direct visualization of 136 treated influenza virions at pH 7.5 or acidified to pH 5.0 showed that virions remain intact and that glycoproteins become disorganized as expected when HA undergoes a conformational change. This suggests that exposure of the fusion peptide at low pH is not inhibited but lipid mixing is inhibited, a different mechanism than previously reported fusion inhibitors. We hypothesize that this new class of inhibitors intercalate into the virus envelope altering the structure of the viral envelope required for fusion to cellular membranes.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/57899
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